The Crystal Structure of ATP-bound Phosphofructokinase from Trypanosoma brucei Reveals Conformational Transitions Different from those of Other Phosphofructokinases

The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as well as with those of bacterial ATP-dependent and PPi-dependent PFKs. The active si...

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Bibliographic Details
Published in:Journal of molecular biology 2009-02, Vol.385 (5), p.1519-1533
Main Authors: McNae, Iain W., Martinez-Oyanedel, José, Keillor, Jeffrey W., Michels, Paul A.M., Fothergill-Gilmore, Linda A., Walkinshaw, Malcolm D.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
allostery
Amino Acid Sequence
Animals
Binding Sites
Crystallography, X-Ray
eukaryote
Fructosephosphates - metabolism
Isoenzymes - chemistry
Isoenzymes - metabolism
Models, Molecular
Molecular Sequence Data
phosphofructokinase
Phosphofructokinases - chemistry
Phosphofructokinases - metabolism
Protein Conformation
Protozoan Proteins - chemistry
Protozoan Proteins - metabolism
Trypanosoma brucei
Trypanosoma brucei brucei - enzymology
trypanosomes
X-ray crystallography
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Summary:The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as well as with those of bacterial ATP-dependent and PPi-dependent PFKs. The active site of T. brucei PFK (which is strictly ATP-dependent but belongs to the PPi-dependent family by sequence similarities) is a chimera of the two types of PFK. In particular, the active site of T. brucei PFK possesses amino acid residues and structural features characteristic of both types of PFK. Conformational changes upon ATP binding are observed that include the opening of the active site to accommodate the two substrates, MgATP and fructose 6-phosphate, and a dramatic ordering of the C-terminal helices, which act like reaching arms to hold the tetramer together. These conformational transitions are fundamentally different from those of other ATP-dependent PFKs. The substantial differences in structure and mechanism of T. brucei PFK compared with bacterial and mammalian PFKs give optimism for the discovery of species-specific drugs for the treatment of diseases caused by protist parasites of the trypanosomatid family.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2008.11.047